The present invention comprises compounds useful in treating and/or preventing diseases, such as Tumor Necrosis Factor α (TNF-α), IL-1β, IL-6 and/or IL-8 mediated diseases and other resulting diseases. In particular, the compounds of the invention are useful for the treatment and/or prevention of diseases or conditions involving inflammation.
TNF-α is upstream in the cytokine cascade of inflammation. As a result, elevated levels of TNF-α may lead to elevated levels of other inflammatory and proinflammatory cytokines, such as IL-1, IL-6 and IL-8.
TNF-α and Interleukin-1 (IL-1) are pro-inflammatory cytokines secreted by a variety of cells, including monocytes and macrophages, in response to many inflammatory stimuli (e.g. lipopolysaccharide-LPS) or external cellular stress (e.g., osmotic shock and peroxide).
Elevated levels of TNF-α and/or IL-1 over basal levels have been implicated in mediating or exacerbating a number of disease states including rheumatoid arthritis; inflammatory bowel disease (IBD) including but not limited to Crohn's disease, ulcerative colitis and colitis; Pagets disease; osteoporosis; multiple myeloma; uveitis; acute and chronic myelogenous leukemia; pancreatic β cell destruction; rheumatoid spondylitis; osteoarthritis; gouty arthritis and other arthritis conditions; gout; adult respiratory distress syndrome (ARDS); chronic pulmonary inflammatory diseases; silicosis; pulmonary sarcoidosis; psoriasis; rhinitis; anaphylaxis; contact dermatitis; pancreatitis; asthma; muscle degeneration; cachexia such as cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome; Reiter's syndrome; type I diabetes; bone resorption disease; graft vs. host reaction; ischemia reperfusion injury; brain trauma; multiple sclerosis; cerebral malaria; sepsis; septic shock; toxic shock syndrome; endotoxic shock; gram negative sepsis; fever and myalgias due to infection such as influenza; pyrosis.
TNF-α and IL-1 appear to play a role in pancreatic β cell destruction and diabetes. Pancreatic β cells produce insulin which helps mediate blood glucose homeostasis. Deterioration of pancreatic β cell functional abnormalities may occur in patients with type II diabetes.
Administration of TNF-α into the rat cortex has been reported to result in significant neutrophil accumulation in capillaries and adherence in small blood vessels. TNF-α promotes the release of other cytokines (IL-1β, IL-6) and also chemokines, which promote neutrophil infiltration into the infarct area (Fleurstein, Stroke 25, 1481 (1994).
In rheumatoid arthritis models in animals, multiple intra-articular injections of IL-1 have led to an acute and destructive form of arthritis (Chandrasekhar et al., Clinical Immunol Immunopathol. 55, 382 (1990)). In studies using cultured rheumatoid synovial cells. IL-1 is a more potent inducer of stromelysin than TNF-α (Firestein, Am. J. Pathol. 140, 1309 (1992)). At sites of local injection, neutrophil, lymphocyte, and monocyte emigration has been observed. The emigration is attributed to the induction of chemokines (e.g., IL-8), and the up-regulation of adhesion molecules (Dinarello, Eur. Cytokines Netw. 5, 517-531 (1994)).
IL-8 has been implicated in exacerbating and/or causing many disease states in which massive neutrophil infiltration into sites of inflammation or injury (e.g., ischemia) is mediated by the chemotactic nature of IL-8, including, but not limited to, the following: asthma, inflammatory bowel disease (ITBD), psoriasis, adult respiratory distress syndrome, cardiac and renal reperfusion injury, thrombosis and glomerulonephritis. In addition to the chemotaxis effect on neutrophils, IL-8 also has the ability to active neutrophils. Thus, reduction in IL-8 levels may lead to diminished neutrophil infiltration.
TNF-Γ and IL-1 affect a wide variety of cell and tissues and these cytokines as well as other leukocytes derived cytokine, such as IL-6 and IL-8, are important and critical inflammatory mediators of a wide variety of diseases states and conditions. The inhibition of these cytokines is of benefit in controlling, reducing and alleviating many of these disease states mediated by these cytokines.
Several approaches have been taken to block the effect of TNF-α. One approach involves using soluble receptors for TNF-α (e.g. TNFR-55 or TNFR-75), which have demonstrated efficacy in animal models of TNF-α-mediated disease states. A second approach to neutralizing TNF-α using a monoclonal antibody specific to TNF-α, cA2, has demonstrated improvement in swollen joint count in a Phase I human trial of rheumatoid arthritis (Feldmann et al.; Immunological Reviews, pp. 195-223 (1995)). These approaches block the effects of TNF-α and IL-1 by either protein sequestration or receptor antagonism.
In certain cases, these approaches do not provide effective relief for some sufferers of inflammatory disease and cause adverse effects. Thus, there is currently a need for new anti-inflammatory pharmaceuticals.
GPR43 (also named FFA2R) belongs to a subfamily of G-Protein-Coupled Receptors (GPCRs), including GPR40 and GPR41 that have been identified as receptors for free fatty acids (Le Poul et al., J. Biol Chem. 278, 25481-489, 2003; Covington et al., Biochemical Society transaction 34, 770-773, 2006). The 3 family members share 30 to 40% sequences identity with specificity toward different fatty acids carbon chain length, with short chain fatty acids ((SCFAs): six carbons molecules or shorter) activating GPR41 and GPR43 and medium and long chain fatty acids activating GPR40 (Rayasam et al., Expert Opinion on therapeutic targets, 11 661-671, 2007). C2 acetate and C3 propionate are the most potent activators of GPR43.
GPR43 is strongly expressed in peripheral blood mononuclear cell (PBMC), bone marrow, and polymorphonuclear cells such as neutrophils. The involvement of GPR43 in leukocyte function is supported by the induction of its mRNA during the differentiation and activation of monocytes and neutrophils cells (Le Poul et al., J. Biol. Chem., 2003, 278: 25481-25489; Senga et al., Blood, 2003, 101: 1185-1187). Recent studies have shown that both acetate and propionate decreased LPS-stimulated TNF-α release from neutrophils. In addition propionate dose-dependently suppressed IL-6 mRNA and protein release from colitis mouse colon organ cultures. TNF-α and members of the interleukin family are known to play a key role in the pathogenesis of IBD (Fuss, Curr Drug Targets Inflamm allergy 2003, 2: 101-112; Tedelind et al., World J Gastroenterol 2007, 13(20): 2826-2832). Further, GPR43 has been described to regulate the anti-inflammatory responses by SCFA in various in vivo model such as colitis, rheumatoid arthritis and asthma through a regulation of the neutrophil physiolology. SCFA-mediated GPR43 activation decreased TNF-α and MIP-1α levels in mouse DSS colitis model, as well as neutrophil chemotactic responsiveness (Maslowski et al, Nature, 2009, 461(7268): 1282-1286). Taken together these results suggest that therapeutic strategies based on GPR43, the major receptor for acetate and propionate for which anti-inflammatory properties have been clearly demonstrated, could be useful in treatment of inflammatory diseases.
On this basis, GPR43 agonists or partial agonists may be of therapeutic value for the treatment and/or prevention of inflammatory diseases.